We humans are fragile or so as most people would experience. Injuries, such as falling, traffic accidents, cuts or any form of accidents big or small can’t be predicted but also unavoidable parts of life.
These minor wounds are harmless to a person because they always heal in a short time. However, in people with diabetes, these wounds can take longer to heal. This slow healing can increase a person’s risk of developing infections and other complications, making wounds become a harsh issue.
Wound healing is classically divided into 4 stages, hemostasis, inflammation, proliferation, and remodeling.
The first step of hemostasis occurs immediately after injury and involves vascular constriction for reducing blood loss, as well as platelet aggregation and fibrin formation. Aggregated platelets within the clot form also the basic structure for the recruitment of inflammatory cells and, through the release of several cytokines and growth factors, including platelet-derived growth factor (PDGF) and transforming growth factor β (TGFβ), they attract different cell types and driven the wounds to the next stage.
In the inflammation stage, after blood loss is under control, neutrophils, macrophages, and lymphocytes accumulate on the wound bed. The main function of neutrophils is to remove pathogens and excess cellular debris, but they also generate reactive oxygen species (ROS) ,which is a common group of free radicals, during the eliminating process.
Macrophages can release cytokines to promote inflammatory response, inducing apoptosis, and then work with leukocytes to remove these apoptotic cells and promote tissue regeneration.
In the third step, the proliferation of cells mostly overlaps with the inflammatory period. At the same time as inflammation, angiogenesis, epithelial cell division and migration, and collagen and extracellular matrix will proliferate together.
Finally, the newly formed collagen undergoes remodeling, and the blood vessels gradually mature and degenerate[1].
Diabetes mellitus is a chronic heterogeneous metabolic disorder caused by abnormal insulin secretion, insulin action, or both, which is characterized by excessive blood glucose concentration in patients[2].
According to the International Diabetes Federation,IDF, in 2021, 537 million adults (20-79 years) in the world had diabetes, compared with 366 million in 2011[3]. Over the past three years, the prevalence of type 2 diabetes has increased dramatically in countries of all income levels. According to statistics from the Central Health Insurance Administration of the Ministry of Health and Welfare, in Taiwan, in 2018, health care expenditures on diabetes amounted to 29.1 billion, second only to chronic kidney disease[4].
In a well-known disease, diabetes, for these patients, wound repair is very difficult and can even lead to other serious problems.
According to one estimate [5], about one-third to one in five people with diabetes develop chronic non-healing wounds, especially on the feet and joints. Such as foot ulcers and Charcot’s joints, a kind of osteoarthropathy.
Excessive blood sugar concentration in the blood of diabetic patients will increase the inflammatory response of the body's cells, and cause lesions in the peripheral nerves and vascular systems while reducing the body's ability to respond to the immune system. Sustained high blood sugar will cause the electron transport chain in the mitochondria to produce excessive amounts of reactive oxygen species (ROS), which leads to the imbalance of oxidation and antioxidant systems, which in turn affects the normal redox reaction of cells[5]. In addition, non-healing wounds for a long time not only increase the risk of infection but also increase the psychological stress of patients.
We know that Cofactor Q10 is used as a treatment for type 2 diabetes. The proximity of mitochondria to ROS will cause oxidative stress, and Cofactor can scavenge free radicals[6], such as the ROS mentioned above, this characteristic inspired us to use cofactors in wound dressings to accelerate wound healing, so we want to use cofactors, Pyrroloquinoline quinone, PQQ, and test its efficacy on cell repair and accelerated wound healing. PQQ is a redox cofactor and an antioxidant factor. First, it acts as a ROS scavenger, which can help reduce oxidative stress within wounds. Furthermore, it can promote mitochondrial regeneration. Finally, as an anti-inflammatory substance, PQQ can reduce the inflammatory effect caused by high blood sugar concentrations.
Last year, the iGEM team NCHU-Taichung tested the application of PQQ in the growth of plant cells and found that it can promote the growth of plants, so we wondered whether PQQ could also promote the growth of animal cells, or even promote wound repair.
After knowing these special properties of PQQ, we started to look for a platform that is safe enough and suitable for humans to produce it. And Bacillus subtilis natto is our answer.
Bacillus subtilis can coexist in the human intestine, and the Bacillus subtilis natto we use is its subspecies. A Japanese food, natto, is fermented with Bacillus subtilis natto, which is already a common probiotic in our lives. Moreover, the metabolites of Bacillus subtilis natto are also helpful for wound repair. For example, γ-PGA has a moisturizing effect, keeping the wound moist to a certain extent can accelerate wound healing. Vitamin K2 promotes blood coagulation and helps to accelerate wound healing. So we chose Bacillus subtilis natto as our strain for producing PQQ.
Given the increasing number of diabetic patients and the difficulty of wound healing, we wanted to develop a dressing to promote the repair of chronic wounds, which would benefit a large number of diabetic patients in the world or more patients with chronic wound problems. We expect dressings like this to contribute to and change our life.
References
-
Guo, S., & Dipietro, L. A. (2010). Factors affecting wound healing. Journal of dental research, 89(3), 219–229.
https://doi.org/10.1177/0022034509359125 -
Banday, M. Z., Sameer, A. S., & Nissar, S. (2020). Pathophysiology of diabetes: An overview. Avicenna journal of medicine, 10(4), 174–188.
https://doi.org/10.4103/ajm.ajm_53_20 -
International diabetes federation. (2021, September 12). Diabetes Facts & Figures. International Diabetes Federation.
https://idf.org/aboutdiabetes/what-is-diabetes/facts-figures.html -
中央社. (2019, September 2). 健保醫療支出10大疾病排行榜出爐！慢性腎臟病蟬聯冠軍，年花健保513億. The Storm Media風傳媒.
https://www.storm.mg/article/1662833 -
Burgess, J. L., Wyant, W. A., Abdo Abujamra, B., Kirsner, R. S., & Jozic, I. (2021). Diabetic Wound-Healing Science. Medicina (Kaunas, Lithuania), 57(10), 1072.
https://doi.org/10.3390/medicina57101072 -
Shen, Q., & Pierce, J. D. (2015). Supplementation of Coenzyme Q10 among Patients with Type 2 Diabetes Mellitus. Healthcare (Basel, Switzerland), 3(2), 296–309.
https://doi.org/10.3390/healthcare3020296
